The importance of sleep in human health is well-described, as loss of sleep is associated with neurobehavioral, cardiovascular, and metabolic consequences. Furthermore, sleep disorders are increasingly recognized to be common, and indeed, it has been estimated that billions of dollars are spent each year as a result of these disorders. Despite this, our understanding of the basic function of sleep, as well as the molecular and cellular pathways underlying sleep, remain poorly understood, which limits our ability to identify new therapeutic targets for treatments of sleep disorders. The overall goal of this research application is to understand the molecular and genetic basis of sleep regulation, using the fruit fly Drosophila melanogaster as a model system. The use of Drosophila as a genetic model system has led to many fundamental discoveries, such as the unlocking of the molecular mechanisms underlying circadian rhythms. Fruit flies have also been demonstrated to engage in sleep behavior, and many of the signaling pathways between flies and humans are conserved. Thus, fruit flies are well-suited for the identification of novel genes and molecules that regulate sleep. Using a genetic screen in Drosophila, we have identified a novel mutant, named wide awake (wake), which exhibits a significant reduction in sleep, and a prominent increase in sleep latency (i.e., they take much longer to fall asleep). Our preliminary studies suggest that the WAKE protein is expressed in a neuronal circuit that promotes arousal and that the normal function of WAKE is to enhance GABA signaling and inhibit the circuit in which it is expressed. In this application, we will increase our understanding of the molecular and cellular basis of sleep regulation by carrying out the following aims: 1) investigate the regulation and localization of WAKE protein, 2) identify the neuronal circuits required for WAKE function, and 3) determine the mechanisms by which WAKE regulates sleep. These studies will enhance our understanding of a novel molecule that regulates sleep, and, because most signaling pathways regulating sleep between flies and mammals are conserved, should yield insights into the molecular mechanisms underlying sleep in humans. PUBLIC HEALTH RELEVANCE: Sleep disorders are common, but our limited understanding of the molecules that regulate sleep impedes our ability to identify new targets for treatments. This study will characterize a novel molecule that regulates sleep, and may thus lead to new targets for therapies of sleep disorders.